Pulmonary hypertension (PH) is a life-threatening condition which can occur in association with many diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). PH occurring in isolation, with characteristic remodeling of pulmonary muscular arterioles, is classified as pulmonary arterial hypertension (PAH). The mechanistic pathways leading to PH are poorly understood. We have performed genome-wide RNA expression profiling in lung tissue from 18 PAH subjects, 8 subjects with PH secondary to IPF, and 13 normal subjects. With this approach, we have identified several biological pathways that are perturbed in PAH and PH secondary to IPF relative to normal controls. The mechanisms of PH secondary to COPD remain unclear. No systematic genome-wide study has been performed to identify all biological pathways that are perturbed in PH secondary to COPD, and to determine whether these pathways are common to other forms of PH. The overall goal of this proposal is to determine which genetic, molecular, and cellular mechanisms are specific to PH secondary to COPD, or shared with PAH and PH secondary to IPF. We propose to study lung tissue specimens from the Lung Tissue Research Consortium (LTRC) from (1) subjects with COPD and a DLCO <30% of predicted and plasma BNP >40 pg/ml (associated with secondary PH) and (2) subjects with COPD and a DLCO >70% of predicted and plasma BNP <30 pg/ml (associated with normal pulmonary artery pressures [PAP]). We hypothesize that comparative genome-wide RNA expression analysis of two COPD cohorts from the LTRC (with and without PH) and our previously characterized cohorts (PAH, PH secondary to IPF, and normal controls) will identify both biological pathways common to all forms of PH and others specific to each underlying disease. Accordingly, the specific aims of this proposal are: 1. To acquire and to compare RNA expression profiles in lung tissue from the following cohorts: a. COPD and secondary PH (DLCO <30% of predicted and plasma BNP >40 pg/ml) from the LTRC;b. PAH from the University of Pittsburgh;c. PH secondary to IPF from the University of Pittsburgh;d. Normal controls from the University of Pittsburgh;e. COPD and normal PAP (DLCO >70% of predicted and plasma BNP <30 pg/ml) from the LTRC. 2. To confirm at the protein level changes in key biological pathways identified under Specific Aim 1 using immunoblots, lung tissue protein microarrays, and immunofluorescence. PUBLIC HEALTH RELEVANCE: Pulmonary hypertension (PH) is a life-threatening disease which can occur alone or in association with other lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Even with the best treatments, only about half of patients survive five years after diagnosis. This project will analyze the way genes are expressed in their lungs, to determine how this disease develops and to identify ways of curing it. (End of Abstract)